MTI-101 is a cyclic beta-hairpin peptide that binds CD44 with high affinity and kills multiple myeloma cell lines in vitro and blocks the growth of myeloma tumors in 2 different murine models. This interaction of MTI-101 with the surface of MM cells causes programmed cell necrosis, whereas all approved MM drugs cause apoptosis and so the novel mechanism of MTI-101 or MTI-like compounds makes it especially attractive for further development. The focus of this application will be on the synthesis and biological evaluation of MTI- 101-like analogs based on a novel peptoid-peptide hybrid scaffold. The following Aims are also the Milestones for this phase I application; they must be completed before a phase II application can be submitted. Aim 1. We will prepare focused libraries that vary the norLeu group with at least 50 different primary amines. The one with the best binding and in vitro bioactivity will be left unchanged and in turn the Val and the Trp positions will be optimized with at least 50 different primary amines. Milestone 1 prepare/screen e150 analogs. Aim/Milestone 2. We will structurally characterize representative members of this e150-membered library using 2D NMR experiments to verify that the expected cyclic beta-hairpin-like conformation is adopted. We will verify that these peptoid-peptide MTI-101 analogs will have improved bioavailability relative to the all peptide MTI-101 by measuring the logp on selected analogs and comparators without the hybrid peptoid-peptide backbone. We will test the preliminary PK characteristics of MTI-101 peptoid analogs with equivalent or improved binding and in vitro activity and compare with the peptidic MTI-101. Aim/Milestone 3. An optimized MTI-101-like peptoid-peptide scaffold will be tested in a 5TGM1 animal model.